Surgically implanted devices having reduced scar tissue formation

ABSTRACT

An anti-proliferative drug, such as rapamycin or taxol, is placed onto or within a sheet of material or mesh. The strands onto or into which the drug is placed may be either a permanent implant or it may be biodegradable. Surgical sutures or staples may also be coated and used for connecting human tissues (i.e., for example, an anastomosis).

REFERENCE TO A PREVIOUS PATENT APPLICATION

This is a continuation-in-part application of the patent application Ser. No. 09/705,999 filed on Nov. 6, 2000.

FIELD OF USE

This invention is in the field of materials used to prevent the formation of scar tissue subsequent to a surgical procedure or accidental skin cut of a human subject.

BACKGROUND OF THE INVENTION

Post-operative adhesions are a major problem following abdominal and other surgical procedures. These adhesions are caused by the unwanted proliferation of scar tissue between internal tissues and structures of the human body generally after surgery. Several companies have developed sheets of biodegradable mesh that can be placed between these structures to reduce the tissue growth. None are entirely effective as some scar tissue typically grows through the mesh. U.S. Pat. No. 5,795,286 describes the use of a beta emitting radioisotope to reduce the proliferation of tissue through a biocompatible material placed into the human body. Although radioisotopes may be effective at preventing the cell proliferation associated with adhesions, the limited shelf life and safety issues associated with radioisotopes makes them less than ideal for this purpose.

Recent publications (Transcutaneous Cardiovascular Therapeutics 2000 Abstracts) report a greatly reduced cell proliferation within angioplasty injured arteries when vascular stents used for recannalization are coated with an anti-proliferative drug such as Rapamycin (Sirolmus) or Taxol. However, these drugs have never been used for reducing cellular proliferation of tissues separated by a surgical procedure.

SUMMARY OF THE INVENTION

A first embodiment of this invention is a device consisting of a drug impregnated into, coated onto or placed onto a material sheet or mesh designed to be placed between internal body tissues that have been surgically separated to prevent the formation of post-operative adhesions, which adhesions are really scar tissue formation. A drug that is impregnated into a gauze-like material or coated onto the material or joined to the material by adhesion and/or capillary action is defined herein as a drug “attached” to a mesh. This mesh or gauze onto which the drug is attached may be either a permanent implant or it may be biodegradable. The drug can be attached to an existing product such as the Johnson & Johnson SURGICEL™ absorbable hemostat gauze-like sheet. With an anti-proliferative drug such as Rapamycin or Taxol which have a known effect on proliferating cells, the biodegradable mesh would decrease cellular proliferation and hence be a deterrent to the formation of adhesions. It is also envisioned that an anti-proliferative drug attached to a bandage could be placed onto a cut in the skin for reducing scar tissue formation. This cut could be accidental or a result of a surgical incision. It is also envisioned that an anti-proliferative drug could be attached to surgical suture material that is used (for example) to join together two blood generally cylindrical cavitys, i.e., an anastomosis, with the attached drug causing a reduction in cellular proliferation in the vicinity where the sutures penetrate through the human tissue. It should be understood that the suture material could be either soluble or insoluble and could be used for any application for which sutures are used. Still another embodiment of the present invention is an anti-proliferative drug coated onto a surgical staple thus reducing scar tissue around that staple. Still another embodiment of this invention is to attach an anti-proliferative drug to a device such as a buckle that is used for the treatment of a detached retina. Since scar tissue formation is one of the main complications of a retinal attachment procedure, by attaching an anti-proliferative drug to the buckle that is placed around the eye, there can be some reduction in scar tissue formation. It is also envisioned to attach an anti-proliferative drug attached to the outside of a cylindrical tube that is placed within a generally cylindrical cavity of the human body to decrease scar tissue formation after a surgical procedure on that generally cylindrical cavity. Such a generally cylindrical cavity might be a nostril after an operation for a deviated septum, a fallopian tube, a billiary duct, a urethra, (for example after prostate surgery) a ureter, a bronchial tube, etc. For such an application, the tube with the attached anti-proliferative drug could be biodegradable, remain implanted or it could be removed after a few days or weeks.

Another device that would benefit from a coating of an anti-proliferative agent such as Rapamycin is a prosthetic implant that is placed into a woman's breast after reconstructive or augmentative surgery. Breast implants typically form significant scar tissue around their surface after implantation. Coating the surface of the breast implant with a slowly releasing anti-proliferative agent can significantly reduce this scar tissue formation.

Still another application of these concepts is for aterio-venous fistulas that are used for kidney dialysis patients. These devices (which are also called a-v shunts) are used to connect an artery in an arm to a large vein in the same arm. The plastic a-v shunt is then penetrated by comparatively large needles through which the patient's blood is cleansed typically every other day. A frequent cause of failure for these shunts is caused by proliferative cell growth at the anastamosis where the shunt is joined to a vein. By having sutures coated with an anti-proliferative agent and by coating the interior and/or exterior of the a-v shunt with an anti-proliferative agent it is expected that the time for maintaining adequate blood flow through the vein will be extended.

In addition to applying the anti-proliferative drug by means of a device to which the anti-proliferative drug is attached, it is also envisioned to apply the anti-proliferative drug systemically by any one or more of the well known means for introducing a drug into a human subject. For example, an anti-proliferative drug could be applied by oral ingestion, by a transdermal patch, by a cream or ointment applied to the skin, by inhalation or by a suppository. Any of these methods being a systemic application of an anti-proliferative drug. It should be understood that such a drug should be applied systemically starting at least one day prior to a surgical procedure but could be started as long as 5 days prior to a surgical procedure. Furthermore, the drug should be applied for a period of at least one day after the procedure and for some cases as long as 60 days. It should be understood that an anti-proliferative drug could be given systemically without using any of the devices described herein. Preferably, the anti-proliferative drug would be given systemically in addition to the application of an anti-proliferative drug attached to any one or more of the devices described herein. It should also be understood that an optimum result might be obtained with using one anti-proliferative drug attached to a device with a second and/or third drug being used for systemic administration. A typical dose for a patient, for example with Rapomycin, would be 1.5 mg/kg per day. The dose would of course depend on the anti-proliferative drug that was used.

Thus it is an object of this invention to have a sheet of material that can be placed between internal body tissues, the material having an anti-proliferative drug attached to reduce scar tissue formation between adjacent layers of the human tissue.

Another object of this invention is to have a biodegradable sheet of material or mesh suitable for placement between body tissues including an attached drug that prevents the cellular proliferation associated with post-surgical adhesions.

Still another object of the invention is to have a bandage to which an anti-proliferative drug is attached that is placed onto a cut in the skin to reduce scar tissue formation.

Still another object of the invention is to have a suture material or surgical staple to which an anti-proliferative drug is attached.

Still another object of the invention is to have an anti-proliferative drug attached to the exterior of a cylindrical tube that is placed into a generally cylindrical cavity of the human body after a surgical procedure on that generally cylindrical cavity.

Still another object of the invention is to have a device implanted in a human subject, the device having an anti-proliferative agent attached; the device being a breast implant, an a-v shunt or an equivalent device for implantation into the human subject.

Still another object of this invention is to have the anti-proliferative drug be Rapamycin or an equivalent drug.

Still another object of this invention is to have the anti-proliferative drug be Taxol or an equivalent drug.

Still another object of the invention is to employ a device placed into or onto the body of a human subject, which device has an attached anti-proliferative drug, plus using the same or a different anti-proliferative drug as a medication to be applied systemically to the human subject from some time prior to a surgical procedure to some time after that procedure.

These and other objects and advantages of this invention will become obvious to a person of ordinary skill in this art upon reading of the detailed description of this invention including the associated drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a plan view of a sheet or mesh onto which an anti-proliferative drug has been attached.

FIG. 2 is an enlargement of the cross section of a single strand of the mesh where the drug is embedded within the strand.

FIG. 3 is an enlargement of the cross section of a single strand of the mesh where the drug is coated onto the strand.

FIG. 4 is an enlargement of two strands of the mesh that have been dipped into a solution of an anti-proliferative drug thereby attaching the drug to the strands by adhesion and capillary action.

FIG. 5 shows a cross section of the mesh to which an anti-proliferative drug has been attached, the mesh being placed between two layers of tissue of the human body.

FIG. 6 is a cross section of the skin onto which is taped a bandage to which an anti-proliferative drug has been attached.

FIG. 7 is a cross section of a human breast into which a breast implant has been placed.

DETAILED DESCRIPTION OF THE DRAWINGS

FIG. 1 shows an absorbable hemostat mesh sheet 10 with mesh strands 12 and open spaces 11. The sheet 10 is designed to be placed post-operatively between internal body tissues that have been separated by a surgical procedure. The mesh strands 12 can be made from oxidized regenerated cellulose or other biodegradable materials with the anti-proliferative drug either embedded within the strands, coated onto the outer surfaces of the strands or held onto the strands by adhesion or capillary action. Any of these possibilities will be described herein as the drug being attached to the mesh or attached to the strand of the mesh.

FIG. 2 is an enlargement of a cross section of a single strand 12 of the mesh 10 in which the anti-proliferative drug 14 is embedded within the strand 12.

FIG. 3 is an enlargement of the cross section of a single strand 12 of the mesh where the anti-proliferative drug 17 is coated onto the exterior surface of the strand.

FIG. 4 is an enlargement of two adjacent strands 12 of the mesh 10 onto which an anti-proliferative drug 18 is attached by means of adhesion and capillary action.

FIG. 5 shows the anti-proliferative drug attached to the mesh 10 placed between two adjacent tissues 20 and 21 of a human body. The mesh 10 would be inserted during a surgical procedure typically just before closing of the surgical incision. When the biodegradable mesh 10 dissolves or is absorbed into the tissues 20 and 21, the anti-proliferative drug attached to the mesh 10 will become dispersed into the tissues 20 and 21. On the other hand, if the biocompatible sheet of material is not biodegradable, the anti-proliferative drug will remain at the site where it is placed for a longer period of time than if the material sheet is biodegradable. Similarly, the drug itself may be produced in a soluble or insoluble form. An insoluble form would remain at the treatment site longer than a soluble form.

The anti-proliferative drugs that may be used include cancer drugs such as Taxol and other known anti-proliferative drugs such as Rapamycin. Other drugs that could be used are Alkeran, Cytoxan, Leukeran, Cis-platinum, BiCNU, Adriamycin, Doxorubicin, Cerubidine, Idamycin, Mithracin, Mutamycin, Fluorouracil, Methotrexate, Thoguanine, Toxotere, Etoposide, Vincristine, Irinotecan, Hycamptin, Matulane, Vumon, Hexalin, Hydroxyurea, Gemzar, Oncovin and Etophophos, taclolimus (FK506), and the following analogs of sirolimus: SDZ-RAD, CCI-779, 7-epi-rapamycin, 7-thiomethyl-rapamycin, 7-epi-trimethoxyphenyl-rapamycin, 7-epi-thiomethyl-rapamycin, 7-demethoxy-rapamycin, 32-demethoxy, 2-desmethyl and proline.

Although a mesh has been discussed herein, more generally, an anti-proliferative drug can be made to be part of any sheet of material that is or is not biodegradable, as long as the sheet of material is biocompatible. In any case the effect of the anti-proliferative drug that is attached to at least part of the sheet of material will decrease cellular proliferation and therefore decrease the formation of scar tissue and adhesions.

It should also be understood that the mesh 10 could be rolled into a cylinder and placed into a generally cylindrical cavity of the human body that has undergone a surgical procedure. The mesh 10, in a cylindrical form, could also be placed around an elastomer tube prior to placement in the human generally cylindrical cavity.

FIG. 6 is a cross section of a cut 23 in the skin 22 that is situated above the subcutaneous tissue 24. A bandage 25 to which an anti-proliferative drug has been attached is shown attached to the skin 22 by means of an adhesive tape 26. The purpose of the anti-proliferative drug is to reduce scar tissue formation in order to have an improved appearance of the skin. The bandage may also include an antiseptic agent to decrease the possibility of infection.

It should also be understood that an ointment that includes an anti-proliferative agent could be used separately from the bandage 25 of FIG. 6. The anti-proliferative agent would be selected from the group that includes Alkeran, Cytoxan, Leukeran, Cis-platinum, BiCNU, Adriamycin, Doxorubicin, Cerubidine, Idamycin, Mithracin, Mutamycin, Fluorouracil, Methotrexate, Thoguanine, Toxotere, Etoposide, Vincristine, Irinotecan, Hycamptin, Matulane, Vumon, Hexalin, Hydroxyurea, Gemzar, Oncovin and Etophophos, taclolimus (FK506), and the following analogs of sirolimus: SDZ-RAD, CCI-779, 7-epi-rapamycin, 7-thiomethyl-rapamycin, 7-epi-trimethoxyphenyl-rapamycin, 7-epi-thiomethyl-rapamycin, 7-demethoxy-rapamycin, 32-demethoxy, 2-desmethyl and proline.

Another alternative embodiment of the invention is a suture material to which an anti-proliferative drug is attached. A drawing of a highly enlarged cross section of such a suture would be shown by FIG. 2 or 3. That is, FIG. 2 could be considered to be a cross section of a suture 12 into which is embedded an anti-proliferative drug 14. FIG. 3 could be considered a highly enlarged cross section of a suture 12 that is coated with an anti-proliferative drug 17. The object of attaching an anti-proliferative drug to a suture would be to reduce scar tissue formation where the suture penetrates through human tissue. This would be particularly true for the use a suture to join together two generally cylindrical cavitys, i.e., an anastamosis. This could be used for both soluble and insoluble suture materials. Furthermore, an anti-proliferative drug could be attached to any surgical staple that is used to join together human tissue after a surgical procedure. It should be understood that sutures or staples with an anti-proliferative agent attached could be used for joining any tissue of a human subject where it is desired to reduce cellular proliferation, i.e., the formation of adhesions or scar tissue.

FIG. 7 illustrates the implant into the breast of a human subject of a breast implant 31. Attached to the breast implant 31 would be an anti-proliferative agent selected from the group that includes Rapamycin, Taxol, Alkeran, Cytoxan, Leukeran, Cis-platinum, BiCNU, Adriamycin, Doxorubicin, Cerubidine, Idamycin, Mithracin, Mutamycin, Fluorouracil, Methotrexate, Thoguanine, Toxotere, Etoposide, Vincristine, Irinotecan, Hycamptin, Matulane, Vumon, Hexalin, Hydroxyurea, Gemzar, Oncovin and Etophophos, taclolimus (FK506), and the following analogs of sirolimus: SDZ-RAD, CCI-779, 7-epi-rapamycin, 7-thiomethyl-rapamycin, 7-epi-trimethoxyphenyl-rapamycin, 7-epi-thiomethyl-rapamycin, 7-demethoxy-rapamycin, 32-demethoxy, 2-desmethyl and proline. When a breast implant has an attached anti-proliferative agent, the scar tissue that typically forms around such an implant will be significantly reduced.

If an arterio-venus fistula shunt is placed into the arm of a dialysis patient, then the same type of anti-proliferative agent(s) as described above could be attached to that implanted device to increase the time during which the associated vein in the arm would remain patent.

Another application of the present invention is for prevention of scar tissue formation subsequent to a procedure for attaching a detached retina. This procedure uses what is called a “buckle” placed around the eye to cause re-attachment of the retina. The extent of scar tissue formation after this procedure is performed can be decreased by attaching an anti-proliferative drug to the buckle. The anti-proliferative drug would then find its way into the eye to decrease scar tissue formation.

For any of the applications described herein, the systemic application of one or more of the anti-proliferative agents that have been described could be used conjunctively to further minimize the creation of scar tissue.

Although only the use of certain anti-proliferative agents has been discussed herein, it should be understood that other medications could be added to the anti-proliferative drugs to provide an improved outcome for the patients. Specifically, for applications on the skin, an antiseptic, and/or anti-biotic, and/or analgesic agent could be added to an anti-proliferative ointment to prevent infection and/or to decrease pain. These other agents could also be applied for any other use of the anti-proliferative drugs that are described herein. It is further understood that any human subject in whom an anti-proliferative agent is used plus at least one of the other drugs listed above could also benefit from the systemic administration of one or more anti-proliferative agent that has been listed herein.

Various other modifications, adaptations, and alternative designs are of course possible in light of the above teachings. Therefore, it should be understood at this time that within the scope of the appended claims, the invention can be practiced otherwise than as specifically described herein. 

1. A method of prophylactically treating vasculoproliferative disease, in a vascular structure following the construction of an arterio-venous graft, an arterial-arterial graft or an arterio-venous fistula, the method comprising applying locally and external to the vascular structure, perivascularly, a therapeutic agent-eluting sleeve, the sleeve comprising a biocompatible matrix material imbibed with rapamycin thereby enabling delivery of an antiproliferative effective amount of rapamnycin to the vascular structure.
 2. A method of treating established vasculoproliferative disease in a vascular structure following the construction of an arterio-venous graft, an arterial-arterial graft or an arterio-venous fistula, the method comprising applying locally and external to the vascular structure, perivascularly, a therapeutic agent-eluting sleeve, the sleeve comprising a biocompatible matrix material imbibed with rapamycin thereby enabling delivery of an antiproliferative effective amount of rapamycin to the vascular structure.
 3. A method of treating or preventing vasculoproliferative disease in vascular structures including at least one anastamotic site wherein the vasculoproliferative disease includes tissue encroaching on the lumen of the vascular structure following the construction of arterio-venous grafts, arterial-arterial grafts or aterio-venous fistulae, the method comprising applying locally and external to the vascular structure, perivascularly, adjacent to the site of anastamosis, a therapeutic agent-eluting sleeve, the sleeve comprising a biocompatible matrix material imbibed with rapamycin thereby enabling delivery of an antiproliferative effective amount of rapamycin to the vascular structure.
 4. A method according to claims 1-3 wherein the sleeve is substantially circumvascular.
 5. A method according to claims 1-3 wherein a combination of rapamycin and heparin is administered to the vascular structure.
 6. A method according to claim 5 wherein the amounts of rapamycin and heparin are sufficient to exhibit a synergistic effect in treating vasculoproliferative disease.
 7. A method according to claims 1-3 wherein the amount of rapamycin is about 2 micrograms/cm² to about 10.0 mgs/cm² and the amount of heparin is about 70 units/cm² to about 20,000 units/cm² before contacting the sleeve to the vascular structure.
 8. A method according to claims 12 wherein a combination of rapamycin analogue(s) and heparin is administered to the vascular structure.
 9. A method according to claim 18 wherein the amounts of rapamycin analogues and heparin are sufficient to exhibit a synergistic effect in treating vasculoproliferative disease.
 10. A method according to claim 12 wherein the biocompatabile matrix is biodegradable. 